This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To better understand the mechanisms behind spontaneous miscarriage, to develop therapies for threatened pregnancies, graft acceptance, and cancer immunotherapy. The immunological response to placental MHC class I expression is considered to be important, yet neither the mechanisms nor the significance of this response in humans or nonhuman primates is well understood. Dr. Golos'lab has recently shown that in pregnant rhesus monkeys passively immunized against Mamu-AG, the rhesus nonclassical trophoblast MHC class I molecule thought to be a homolog of HLA-G, there is a broad developmental delay in villous growth and vascularization of the placenta, a disruption of the modification of maternal decidual vessels by invasive extravillous trophoblasts, and altered decidual leukocyte responses to implantation. Hypothesizing that maternal NK cells are critical in the recognition of placental MHC, they now have pilot data demonstrating that NK cell immunodepletion has a negative impact on pregnancy outcome, causing spontaneous abortion within a week after anti-CD16 or anti-CD8 treatment. It is proposed that this is evidence for an important role of placental MHC class I molecules in the maternal immunological response to pregnancy in primates, and will further study the mechanisms and significance of these responses with two specific aims: Specific Aim 1. To determine the effect of immunodepletion of decidual NK cells on implantation, and placental and decidual development in rhesus monkeys. Specific Aim 2. To define the window of placental/decidual sensitivity to NK cell immunodepletion. For this study, the lab will focus on immunodepletion with anti-NK cell antibodies, which deplete CD16-positive or CD8-positive cells, or control antibodies. Aim 1 will define the importance of peripheral NK cell populations in maintaining a stable implantation site in early gestation. Aim 2 will determine if the effects of immunodepletion on pregnancy outcome are restricted to the immediate post-implantation period, and allow us to begin to identify the subpopulation of decidual NK cells not sensitive to peripheral immunodepletion. RELEVANCE TO PUBLIC HEALTH: Placental-maternal immune interactions are hypothesized to contribute to pathological conditions in pregnancy, ranging from infertility and spontaneous miscarriage to preeclampsia. Understanding the importance of these interactions in pregnancy success may guide preclinical studies in potential therapeutic applications of placental MHC molecules, or address the importance of deficiencies or imbalances of endometrial leukocytes in infertility or pregnancy disorders. The nonhuman primate provides a model in which pregnancy is amenable to experimental manipulation. A better understanding of the immune response to the establishment of pregnancy may have significance for understanding spontaneous miscarriage, developing therapies for threatened pregnancies, graft acceptance, and cancer immunotherapy.